In recent years, “tailor made medicine” is gaining recognition, which takes into consideration individual differences between patients, and a search for a marker to distinguish a cancer against which a pharmaceutical agent is effective from a cancer against which the pharmaceutical agent is ineffective is considered to be necessary. It is an attempt to ethically and medically improve cost performance of medication treatment by administering a pharmaceutical agent to patients after verification in advance of the probability of effect thereof, thereby to enhance efficacy as well as avoid toxicity of the pharmaceutical agent, and to reduce insignificant use of the pharmaceutical agent. In cancer treatment, the development of a method for predicting the efficacy of anticancer agents has been desired, because it can be an important means to bridge the gap between basic study and clinical application.
In addition, it has been pointed out with regard to a substance or a compound generally reported to have an antitumor activity that, when the report is based solely on in vitro results, such results do not directly lead to the prediction of in vivo results. In other words, it is a problem that a substance showing an antitumor activity in vitro does not necessarily show an antitumor activity in vivo, and application of a substance showing an antitumor activity in vitro directly as an anticancer agent is difficult.
For example, a compound represented by the formula (II)
has been reported to introduce a potent antitumor activity by selectively inhibiting histone deacetylase (this substance has been also reported to cause high acetylation of histone in a cell treated with this substance, and as a result, induces transcriptional control activity of various genes, cell cycle inhibitory activity and apoptosis inhibitory activity (JP-B-7-64872, H. Nakajima et al, Exp. Cell Res. 241, 126-133 (1998))). However, no report has established a factor capable of predicting an antitumor effect of this compound, and as the situation stands, many problems are yet to be solved, such as whether or not in vitro results directly apply in vivo, whether or not the compound shows a practical effect in vivo in any tumor and the like.
Histone deacetylase is a metallo-deacetylated enzyme wherein Zn is coordinated at the active center (M. S. Finnin et al, Nature, 401, 188-193 (1999)). This enzyme is considered to change the affinity for DNA of various acetylated histones. A direct biological phenomenon this brings about is changes in the chromatin structure. The minimum unit of the chromatin structure is a nucleosome wherein 146 bp DNA is wound 1.8 times anticlockwise around a histone octamer (H2A, H2B, H3 and H4, each 2 molecules, core histone). The core histone stabilizes the nucleosome structure as the positive charge at the N-terminal of each histone protein interacts with DNA. Acetylation of histone is controlled by the balance between the acetylation reaction in which histone acetyl transferase is involved and the deacetylation reaction in which histone deacetylase is involved. The acetylation of histone occurs in an evolutionarily well-preserved lysine residue at the N-terminal of histone protein, whereby, it is considered, the core histone protein loses the charge at the N-terminal, the interaction with DNA is attenuated, and the nucleosome structure becomes instable. Accordingly, the deacetylation of histone is considered to proceed in reverse, namely, toward the stabilization of the nucleosome structure. However, there still remain many unclear aspects such as the degree the acetylation changes the chromatin structure, and how it relates to the secondarily induced transcriptional control and the like.